[Development of a novel gene therapy using survivin antisense expressing adenoviral vectors].

Abstract

BACKGROUND:

Survivin, a novel inhibitor of apoptosis, is undetectable in normal adult tissues but becomes notably expressed in the most common human cancers, and is recognized as a potential target in anticancer therapy.

METHODS:

In this study we evaluated a survivin antisense expressing replication-incompetent adenoviral vector under the control of the cytomegalovirus promoter (pAd.CMV-SAS) for cytoreductive effects in human HT-29 colon cancer cells in vitro and in vivo.

RESULTS:

Infection of tumor cells with pAd.CMV-SAS caused down-regulation of survivin expression and the potential for spontaneous apoptosis in tumor cells. In contrast, pAd.CMV-SAS did not affect cell viability of normal human cells including fibroblasts. In addition, infection of tumor cells with pAd.CMV-SAS resulted in an increase of the G0/G1 phase population in the cell cycle, and increased their sensitivity to chemotherapeutic drugs in vitro. The efficacies of pAd.CMV-SAS were inversely correlated with survivin expression level. In nude mice, pAd.CMV-SAS suppressed tumor formation, as well as decreased the tumor volumes to approximately 30% of the control tumors. Furthermore, it was confirmed that the anti-tumor efficacy of pAd.CMV-SAS was also enhanced in combination with chemotherapeutic drugs in vivo.

CONCLUSIONS:

These findings suggest that targeting of survivin using adenoviral antisense vectors may have a potential role in the selective therapy of colon cancer.

• Authors: Tetsuhisa Yamamoto, Yoshinobu Manome, Akiko Miyamoto, Nobuhiko Tanigawa
• Journal: Gan to kagaku ryoho. Cancer & chemotherapy (Gan To Kagaku Ryoho) Vol. 30 Issue 11 Pg. 1805-8 (Oct 2003) ISSN: 0385-0684 [Print] Japan
• PMID: 14619525 (Publication Type: Journal Article)

Chemical References

• BIRC5 protein, human
• DNA, Complementary
• Inhibitor of Apoptosis Proteins
• Microtubule-Associated Proteins
• Neoplasm Proteins
• Oligonucleotides, Antisense
• Survivin

Topics

• Adenoviridae
• Animals
• Apoptosis
• Cell Cycle
• Cell Division
• DNA, Complementary (biosynthesis)
• Down-Regulation
• Gene Targeting
• Genetic Therapy
• Genetic Vectors
• HT29 Cells
• Humans
• Inhibitor of Apoptosis Proteins
• Mice
• Mice, Nude
• Microtubule-Associated Proteins (biosynthesis, genetics)
• Neoplasm Proteins
• Oligonucleotides, Antisense (therapeutic use)
• Survivin